Mycobacterium leprae is an obligate intracellular parasite that serves as the etiologic agent of leprosy, a disease that afflicts some 15 million individuals worldwide. M. leprae is capable of multiplication in macrophates and can invade and multiply in the Schwann cells in the sheaths of peripheral nerves. In patients with tuberculoid leprosy, the cellular immune response to M. leprae remains intact and these individuals have low titers of circulating antibodies but M. leprae cells are virtually undetectable. Patients with lepromatous leprosy, on the other hand, have a unique suppression of cellular immunity against M. leprae, have high titers of circulating antibody against M. leprae, and have a very hgih bacteriological load. Using recombinant techniques, we have identified cloned genes that express M. leprae protein antigens that react with antibodies in the sera of both lepromatous and tuberculoid leprosy patients. We have also developed some unique avirulent Salmonella strains that are able to stably maintain and express colonization and virulence antigens from other pathogens. Upon oral ingestion, the Salmonella home to the gut-associated lymphoid tissue (GALT) to elicit secretory, humoral and cellular immune responses. We therefore propose to (i) further identify and characterize M. leprae determinants expressed by recombinant Escherichia coli that are recognized by antibodies in sera from lepromatous and/or tuberculoid leprosy patients, (ii) construct avirulent derivatives of S. typhimurium to stably express specific M. leprae antigenic determinants and (iii) immunize mice with these avirulent S. typhimurium recombinant strains to evaluate the quality and duration of secretory, humoral and cellular immune responses against M. leprae. Subsequent work will investigate the induction of immune suppression, the cellular and molecular basis of the cellular immune response, and the use of other animal systems to evaluate induction of protective immunity against M. leprae infection. The methods of biochemistry, immunology, genetics, microscopy, and animal science will be employed in these studies.